Integrated microneedle array and a method for manufacturing thereof

ABSTRACT

The invention relates to a method of manufacturing of a microneedle array comprising the steps of selecting a soft production mold comprising a set of microscopic incisions defining geometry of the microneedles, said soft production mold being capable of providing the microneedle array integrated into a base plate; using a filler material for abundantly filling the microscopic incisions of the soft production mold thereby producing the microneedle array with pre-defined geometry integrated into the base plate; wherein for the filler material a water or alcohol based ceramic or polymer-ceramic slurry is selected. The invention further relates to a microneedle array 16, a composition comprising a microneedle array, a system for enabling transport of a substance through a barrier and a system for measuring an electric signal using an electrode.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.12/922,450, filed on Dec. 6, 2010 as the U.S. National Phase under 35U.S.C. §371 of International Application PCT/NL2009/050118, filed Mar.11, 2009, which claims priority to European Patent Application No.08152571.9, filed Mar. 11, 2008, which are hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

The invention relates to a method of manufacturing a microneedle array.The invention further relates to a microneedle array and a compositioncomprising the microneedle array. The invention still further relates toa system for transporting substances across a material barrier. Theinvention still further relates to a system for measuring of anelectrical signal using an electrode.

BACKGROUND OF THE INVENTION

An embodiment of the microneedle array is known from WO 02/064193. Theknown microneedle array comprises a set of microneedles of a suitablegeometry projecting as an out of plane structure from a base support.The known microneedle array may be produced using conventional methodsused to make integrated circuits, electronic packages and othermicroelectronic devices, which may be augmented by additional methodsused in the field of micromachining and micromolding. The knownthree-dimensional arrays of microneedles can be fabricated usingcombinations of dry-etching processes; micromold creation inlithographically-defined polymers and selective sidewall electroplating,or direct micromolding techniques using epoxy mold transfers. The knownmicroneedle array is formed from a suitable polymer material and can beproduced using (i) etching the polymer microneedle directly, (ii)etching a mold and then filling the mold to form the polymer microneedleproduct, or (iii) etching a microneedle master, using the master to makea mold and then filling the mold to form the polymer microneedle replicaof the master.

Over the recent years more and more microneedles have become popular topenetrate the skin barrier and thus introduce means for creating amicrofluidic pathway across the skin either for drug delivery, or foranalytics of extracted fluids. Microneedles as known in the art may beused in skin patches, in particular in skin patches for delivering adrug across a barrier, for example, skin. So-called intelligent patches,comprising means for delivery of a drug having relatively big molecules,are described in J.-H. Park et al “Polymer particle-based micromoldingto fabricate novel microstructures”, Biomed Microdevices (2007) 9:223-234. However, commercialization of such intelligent skin patcheshaving porosity as an actual functional feature has been difficult dueto lack of inexpensive production method as well as due to lack ofsuitable production materials for patch production with requiredproperties.

The known microneedle production method according to WO 02/064193 has adisadvantage that the method of producing microneedle arrays isrelatively expensive. The method of microneedle production according toJ.-H. Park et al has a disadvantage that the resulting porousmicroneedles are relatively fragile.

SUMMARY OF THE INVENTION

It is an object of the invention to provide an inexpensive and robustmicroneedle array having improved properties, wherein parameters of themicroneedle array can be optimized easily on demand. For example, suchparameters may relate to a tip shape or arrangements of a variety of tipshapes within one array, diameter of the microneedles, their length, aswell as their density in the array. Further on, such parameters mayrelate to chemical or physical properties of a material microneedles arecomposed of.

To this end the method according to the invention comprises the stepsof:

-   -   selecting a soft production mold comprising a set of microscopic        incisions defining geometry of the microneedles, said soft        production mold being capable of providing the microneedle array        integrated into a base plate;    -   using a filler material for abundantly filling the microscopic        incisions of the soft production mold thereby producing the        microneedle array with pre-defined geometry integrated into the        base plate; wherein    -   for the filler material a water or alcohol based ceramic or        polymer-ceramic slurry is selected.

The technical measure of the invention is based on the insight that byusing a suitable soft production mold fabrication of a microneedle arraycan be enabled, whereby microneedles are inherently integrated with thebase plate. The resulting microneedles are porous due to the particularmaterial choice for the filler. It is found that the intrinsic porosityof the microneedle array manufactured according to the invention canenable a suitable tuning of functionality of the microneedles, as thepores may be used as carriers of suitable chemical elements. Thus,porous materials of sufficient strength suitable to overcome a materialbarrier, such as skin, may advantageously add functional features tosystems comprising microneedle arrays. In this respect the microneedlesaccording to the invention solve a further problem of the art—a limitedlevel of functionality of known solid microneedles.

The soft production mold can be produced beforehand in accordance withspecific requirements which have to be met by the microneedle array. Thesoft production mold thereby defines the sought geometry and can berelatively easily produced by methods known in the art. For example, thesoft production mold can be produced using per se known lithographicmethods. The soft production mold is preferably fabricated from apre-defined hard mold using an intermediate mold. Preferably, theintermediate mold is soft.

Additionally, the soft production mold can be formed to enablegeneration of optional microsized features, for example, channels, inmicroneedles by multilevel lithographic processes. In case of channelsthese may convey for suitable high substance transport throughout thebase plate, for example, flow rates of at least 60 μl/h may be achieved.

Such soft-replica is an exact copy of the features produced in the hardmold with little or even no measurable change in dimension ifpolydimethylsiloxane (PDMS) is employed as the soft-lithographymaterial. It has been known in the art that releasing a replica from acomplex three-dimensional shape similar as delivered by the hard moldfor microneedles introduced here, soft-lithography reproduction of theintermediated mold is more reliable (fault-free) and easier to performthan by releasing a hard-replica from a hard mold. This can be explaineddue to relaxation of forces in the flexible body of the replica duringrelease. Basically, this way a soft-replica is peeled off the hard moldusing shear forces instead of only using a one-directional pulling forceas in the case of hard-replica processing. Although such soft-replicacan be deformed during release it remains unaltered in its geometricaldefinition after recovery from the mold, especially when the material ofthe soft replica is elastic. The same reasoning applies for the copyprocess from the intermediate to the production mold as well as from theproduction mold to the green state of the final replicas delivering,after a drying process has been completed, the final integratedmicroneedle array structure. It will be appreciated that the replicarealized by filling ceramic slurry into the production mold will lead torelease of a replica in ceramic green-state, so called green tape.

In case when it is required to modify any of the geometric parameters ofthe microneedle array, like tip shape, diameter and/or length ofindividual microneedles, diameter and configuration of a channel inindividual microneedle, position of a distal opening of the channel withrespect to the tip, density of the microneedles in the array, etc., thesoft production mold may be modified and the replication process cancommence. In this way it suffices to change only the configuration ofthe soft production mold, while keeping the replication processunaltered.

An example of a direct replication process for microneedle arrays from asuitable hard mold utilizing a sacrifical release layer instead offlexible production molds is described in R. Luttge at al “Integratedlithographic molding for microneedle-based devices”, Journal ofMicroelectromechanical systems, Vol. 16, No. 4, 2007. Although thefabrication of silicon hard molds in combination with direct SU-8lithography as described in the aforementioned publication provides alsomicroneedle arrays as a replication result the invention enclosed herereduces the process complexity of the hard mold, yielding a higherreliability in manufacture of the hard mold while increasing theflexibility for customized design changes. Further the invention hereallows easy release from the production mold, i.e. no inconvenientlylong sacrifical etch step is required and no additional auxillaryfeatures are required to allow such sacrifical layer etch. Further thereplication process from the production mold as described in thisinvention is completely independent from a lithographic step, thus thereplication step is also significantly simplified and suitable for veryhigh volume production (mass production of devices). Altogether theadvantages of the present invention significantly increase productionyield for using the production mold in particularly in the replicationof ceramic integrated microneedle arrays. Since the process area perproduction mold is limited by the originally used size of the siliconprocess, for example utilizing a silicon wafer with a 4 inch diameter,the production capacity can be increased by assembling a plurality ofcopies of the production mold into one replication matrices such asknown in the art of very high volume manufacture (for exampleroll-to-roll processes).

In accordance with the invention replication is carried out preferablyusing the soft production mold, as it is found that ceramic or ceramiccomposite material in green state is more fragile than a commonnon-porous polymer material used in replication. A soft-mold furtherguarantees securely (fault-free high yield) release of a ceramic orceramic composite green tape for the manufacture of a microneedle arrayintegrated with the base plate from the production mold.

It will be appreciated that the term ‘integrated’ used in the context ofthe application means that the microneedle structures are inherentlyintegrated with the base plate, i.e. they are formed during the sametechnological step. As a result, the step of assembling the individuallymanufactured microneedles with a separately manufactured base plate, asis known from US 2005/251088, is avoided. As a result the amount ofrelevant production steps of the thus produced microneedle array isreduced and therefore easier as well as less costly to implement inmanufacture, while the intrinsic connection between microneedle and baseplate additionally allows continuous transport characteristic throughoutthe entire microneedle array. These transport characteristic can bedescribed and are of equally high tailorability as found in tortuous(porous) membranes known in the art of membrane technology.

Preferably, in order to further simplify removal of the fabricatedmicroneedle array from the soft production mold, the method according tothe invention comprises the step of coating a surface of the microscopicincisions of the soft production mold with an anti-adhesion layer. Forexample, Teflon or similar materials may be used for this purpose.

It is found that when for the filler material a water or alcohol basedceramic or a polymer-ceramic slurry is selected, a porous ceramic orpolymer-ceramic microneedle array is produced. Such microneedle arraymay have superior physical properties when compared to a known polymeror porous polymer array. In particular the porous microneedle array asprovided by the method according to the invention is more robust leadingto a greater range of dimensions of the individual needles which arefeasible compared to the known microneedle array and providing suitablestrength to penetrate a material barrier such as, for example, skin. Inaddition, the microneedle array provided by the method of the inventiondue to its increased rigidity compared to porous polymer materials canbe removed from the production mold without loss of geometricaldefinition as it is often observed, for example in phase separationprocesses utilizing polymeric replication materials only. The use of aceramic composite in replication, instead of solely polymeric material,provides therefore a higher strength to the replica and thus a reducedrate of production faults. It is appreciate that one notes that thereplica realized by filling ceramic slurry into the production mold willlead to the release of a replica in ceramic green-state, so called greentape. A green tape needs to undergo a distinct drying procedure to beconverted to the full material strength as required to penetrate amaterial barrier such as, for example, skin. When the green tape isrecovered from the soft production mold microneedle arrays can becustomized in terms of sizing the extend of their base plate, forexample, cutting sections from the green tape with the desired aerialdimensions of the patch according to the requirements of a distinctapplication.

In an embodiment of the method according to the invention, the methodcomprises the step of providing one or more microsized channels in themicroneedles of the microneedle array for enabling transport of asubstance through the one or more channels into the base plate or viceversa. Such channels may have dimensions in the order of 10-200micrometer across at least one of its diameters, while its geometricalshape can be defined at will, for example, rectangular, triangular,round, elliptic etc.

For example, one or more projections in the microscopic incisions of thesoft production mold may be provided for forming a fluid channel in oneor more microneedles of the array for conducting a fluid there through.

In case when the microneedle array is conceived to be used for adelivery of a drug or for extraction of a body fluid or the like, it canbe advantageous to provide the microneedle array with an additionalfluid conduit next to the intrinsic porosity of the material. Althoughthe use of porosity only may avoid certain conceived drawbacks ofbackpressure flows with microneedles containing such microsized flowchannel. Configurations, however, will depend up on the specific use ofsuch integrated microneedle arrays. Such conduit can be formed withinthe microneedle array at substantially any place. However, when suchchannel is formed within at least one of the microneedles a relativecentral positioning of the channel is preferred. Additionally, aplurality of protrusions may be provided in the microscopic incisionsfor forming respective channels in the microneedles. It will beappreciated that either a single channel per microneedle or a pluralityof channels per microneedle are contemplated. In this way themicroneedles may be used to administer a suitable drug or for extractinga body fluid achieving higher flow rates (for example inflicted by asuitable pumping mechanism applying vacuum or pressure) than it ispossible by the resulting porosity of the material itself. In furtherrelation to applications such flow channel can provide additionalfunctionality as for example selective elution of a surface-capturedsubstance. For example, elution processes may be utilized in analyticalapplications transferring the captured substance to an analytic device,for example a mass spectrometer. Channels may also be selected in areasof the base plate only. Such openings in the base plate may add tofunctionality of the system, for example when such systems need to befixed to the skin.

In a further embodiment of the method according to the invention, themethod comprises the step of forming respective end portions of themicroscopic incisions on an oblique surface for forming the microneedlearray with oblique tips.

It is found to be advantageous to suitably shape the soft productionmold so that microneedles with oblique tips may be provided. Suchmicroneedles may penetrate the material barrier, like skin, more easily.Such shaping may be enabled using specific crystallographic planes of ahard master mold, as will be discussed in more detail with reference tofigures.

In a further embodiment of the method according to the invention, themethod further comprises the step of adaptively modifying properties ofthe filler material by supplementing the filler material with anadditive.

As a result, it is possible to tailor properties of the microneedlearray by changing characteristics of the filler material. By using anadditive for modifying properties of the ceramic or ceramic compositemicroneedles, the microneedle array produced according to the method ofthe invention can have application-tailorable meso-and macroporosity,specificity of sorption characteristic and tunable interfacialtransport. In the manufacture enclosed here the example of adding Kaolinis presented. A broad variety of such additives may be envisageddelivering nanoscale-defined hybrid materials, incorporating carbonnanotubes, quantum dots, nanoshell particles either with or without acore of either organic or inorganic nature. For example, nanosizedparticles of metallic or inorganic nature may be added to the slurry.Further such tailoring may be carried out in a post-replication step,modifying the green-state by dispensing according substances onto thearray. These modifications may change overall characteristics of thearray material, but may also be seen as an opportunity to introducedifferent modifiers to the material by localized dispensing of suchsuitable additive. Suitable precision liquid dispensing techniques areknown in the art. For example, such application-tailorable propertiesmay be adapted for performing administration of a drug or for diagnosticpurposes. Therefore, the method according to the invention provides arelatively inexpensive solution for mass production of microneedlearrays for a great plurality of application. The thus producedmicroneedle arrays can be used not only for drug delivery or forextraction of a portion of a body fluid, but they can also form part ofan electrode, used for example for myo-stimulation, detection and/ormonitoring of an electrical signal reflective of a vital sign, like EEG,myometry, cardiac activity.

In an embodiment of the method according to the invention for theceramic slurry alumina, zirconia or hydroxyapatite may be selected.

It is found to be advantageous to use these slurries because the moldcan be filled with it quite accurately and the shapes of the formedmicroneedles can be easily recovered from the mold. It is further foundthat physical properties of the ceramic microneedle array, like porositymay be easily tuned when a suitable amount of an additive, such asKaolin, is added to the original slurry. It is found that trace amountof a suitable Si-comprising mineral, like Kaolin may be added to theoriginal slurry. Due to the fact that Kaolin mainly comprises silica,envisaged slurry, for example, silica-alumina nano-composite slurry,creates an interface which results in a mechanically stronger material,because subcrystalline boundaries are created within the bulk of thematerial but also favorably modifies the properties of the green tape,which allows to securely recover the green tape from the productionmold. It is found that when Kaolin is added the sintered ceramicdemonstrates a large transcrystalline fracture behavior, which meansthat it has a stronger grain-boundary than pure alumina resulting in astronger ceramic.

In a further embodiment of the method according to the invention thesoft production mold is manufactured using a double replication of ahard master mold via an intermediate soft mold.

Using such double replication process has an advantage that for purposesof tailoring geometry of the microneedle array the master mold may bechanged leading to a modified soft replication mold, wherein thereplication process from the soft replication mold to the microneedlearray stays unchanged. Thus, once the manufacturing, i.e. replication,technology is optimized it may be kept optimal irrespective of specificgeometric demands of the microneedle array.

Accordingly, it is possible that the hard master mold is firstreplicated into a suitable plurality of soft production molds which maybe disposed of upon use. This has an advantage that the geometry of themicroneedle array defined in the master mold is readily replicable in agreat number of end products without distorting the initial geometry ofthe master mold due to repetitive use thereof. Preferably, the materialof the soft replication mold is elastic. This is advantageous, aselastic material induces less tension on the microneedle array when itis removed from the mold, thereby reducing production losses andimproving quality of the thus produced ceramic or ceramic compositemicroneedle array.

In a still further embodiment of the method according to the inventionthe method further comprises the step of manufacturing the hard mastermold using the steps of:

-   -   disposing a first layer of a radiation sensitive material on a        working surface of a Si-wafer coated with a masking layer;    -   processing the first layer by means of lithography for forming        first openings in the masking layer cooperating with        pre-determined crystallographic planes in the Si-wafer, said        openings having pitch and width;    -   etching the masking layer for forming second openings        cooperating with the first openings;    -   forming a set of cavities in the Si-wafer cooperating with the        second openings;    -   filling the set of cavities in the Si-wafer with a layer of        photoresist;    -   generating a set of inverted microneedles in the layer of the        photoresist.

It will be appreciated that the openings in the Si-wafer may begenerated using a suitable lithographic mask. As a result, a newsequence of technological steps is provided which enables simple meansof changing systematically the tip shape, diameter, the length of asingle needle as well as array density by modifying the planar maskdesign in the photolithographic steps during fabrication of the hardsoft molds (i.e. the intermediate and the production mold) and thereplication process from the production mold to the ceramic integratedmicroneedle array remain unaltered. It will be appreciated that the stepof generating inverted microneedles may be carried out using lithographycomprising the steps of overlaying the openings with a suitable maskcorresponding to a desired shape of the microneedles, exposing anddeveloping the photoresist present in the cavities thereby yielding theinverted microneedles having pitch and width related to the pitch andwidth of the openings. It will be appreciated that when all cavities areused for forming similar sub-sets of microneedles, the pitch of thesub-sets of microneedles may be equal to the pitch of the openings usedto create the cavities. However, it is also possible that not allcavities are used for forming the microneedles, in this case the pitchof the sub-sets of the microneedles may suitably relate to the pitch ofthe openings. Usually, it may be preferred to select the pitch of thesub-sets of the microneedles to follow the pitch of the cavities,however, for example, when sub-sets of four microneedles per cavity aregenerates (see FIG. 7), than the pitch between the individualmicroneedles in the sub-set is different than the pitch of the openings.

Optionally, a multilevel process can be performed by dispensing anadditional photoresist layer on the first exposed layer prior todevelopment, yielding for example additional protrusions in the hardmold after development. Such step may be utilized, for example, to forma microsized channel in the microneedle array.

Preferably for the masking layer used for protection of the siliconwafer during anisotropic etching a Silicon Nitride layer is used. In themethod according to the invention for etching of the masking layerreactive ion etching may be used. In addition, the set of cavities inthe silicon (also refereed to as grooves, pyramidal pits) may be formedusing anisotropic wet etching of the silicon using KOH. As in theexample described here the silicon (100)-working surface is processed,in which the fast etching 100-plane is etched selectively against111-planes. As it is known in the art 111-planes will define the shapeof the anisotropically etched cavity, here, in a pyramidal pit. In themethod of the invention, a thickness of the photoresist layer fillingthe said structures (here pyramidal pits as means of example, generatinga pre-patterned working surface for the subsequent lithographyprocesses) is selected to determine a length of the resultingmicroneedles. Also, the method of the invention may comprise the step ofmodifying the pre-patterned working surface in silicon using ananti-reflection layer prior to dispensing the thick-layer photoresist.Due to this feature ghosting effects in the subsequent lithography stepsresulting from multiple reflections from the oblique surfaces in thepits may be eliminated. Commonly, polymeric layers are known asanti-reflection layers matching SU-8 lithography. However, suchpolymeric layer for example, dispensed by spraying or spinning, willlead to modify the geometrical precision of the pits. A thin-film-typemodification of the working surface is therefore preferred, whensubsequent lithography is carried out on a pre-patterned workingsurface. A suitable thin-film modifier of the said reflection propertiesmay relate to a thin-film titanium silicide layer, which may beprocessed at about 700° C. in nitrogen flow.

Use of lithographic techniques is preferable, because such method isrelatively cheap and enables production of microscopic surfaces withwell defined features, like wall slope, well dimension and the like.Preferably, the first layer of radiation sensitive material forming partof the hard-mold is processed by means of selective irradiation therebysuitably patterning the first layer. It is also possible thatcomplementary to the first layer a second radiosensitive layer isprovided. In this case the method may further comprise the steps ofprocessing the second layer of the material for forming at least onechannel in the microneedles. Such processing is preferably carried outby means of UV-lithography into SU-8 photoresist. With respect tolithographic methods a variety of suitable radiation sources iscontemplated. For example, it is possible to use an electromagneticsource, for example a source generating visible light, (deep)ultra-violet light or even x-ray light, whereas photoresist chemistryhas to be chosen accordingly.

It is possible to selectively irradiate the first layer of material, toprovide a second layer of a material on the selectively irradiated firstlayer of material and to process the second layer of the materialtogether with areas of selective irradiation of the first layer forforming at least one channel in the microneedle array. In this way asuitable feature may be formed in a non-irradiated area of the firstlayer, within the selective irradiation step of the second layer, whereafter the second irradiating step of the features in the first layerwill be developed together with the features in the second layer thusforming together parts of the hard-mold. This is advantageous, becauseit takes less process steps and can easily be implemented thereby savingprocessing time.

It will be appreciated that a method is described with reference to anegative resist. In case when for the radiation sensitive material apositive resist is selected, the respective areas will be inverted sothat portions which are processed will define suitable features of themicroneedle array. By virtue of terminology the negative resist relatesto a radiosensitive material which solubility in a suitable etchantdecreases post illumination. A positive resist relates to aradiosensitive material which solubility increases post illumination.

In a particular embodiment of the method according to the invention thelight source used for lithography may be disposed in such a way throughan according mask (for example a chromium-on-quartz photolithographymask in UV lithography) as to process the first and/or the second layerfor forming the hard-mold containing the inverted shape of a microneedlearray either provided flat or with oblique tips. The embodiment of themicroneedle array consisting oblique tips is particularly suitable forimproving a penetration of the microneedles through a material barrier,for example through a skin barrier. Due to the fact that the tips areoblique with respect a surface of the barrier is being cut on amicroscopic scale. This is advantageous with respect to a tensilepenetration of a flat tipped microneedle array because in the formerreduced skin damage is induced.

It will be appreciated that although examples of specific technologicalprocesses are named, such examples may not be construed as limitation,as a plurality of equivalent or substantially equivalent materialprocessing methods may be applied. Alternatively, in the case of usingx-rays PMMA (polymethyl-metacrylate) may be applied as a radiosensitivelayer.

The microneedle array according to the invention comprises a base plateand a set of microneedles integrated with the base plate, wherein themicroneedles comprise a porous ceramic material or a porous ceramiccomposite material, for example polymer-ceramic or metal-ceramiccomposite.

It will be appreciated that the term ‘composite’ may relate to acomposition comprising at least two elements, whereby one of the said atleast two elements may be present as a trace element. In particular, aceramic material provided with suitable additives for tailoring itsproperties is regarded as a composite ceramic, irrespective of theweight fraction of said additives. Similar to the example using Kaolinother organic or inorganic materials may be used to alter the propertiesof the green-state as well as the final material of the integratedmicroneedle array. One can envisage adding silver or iron, or iron-oxideparticles to the slurry tailoring properties of conductivity ofmagnetizing capabilities within the final device.

Preferably, the microneedle array is fabricated by the method as is setforth in the foregoing. The microneedle array according to the inventioncomprises porous microneedles which are yet robust improving theiruseful properties. For example, the pore size may be selected in therange of sub-nanometer to several nanometers for a microneedle having alength of several tens of micrometers, preferably in the range of 100 to550 micrometers. In addition, the porous ceramic or ceramic compositemicroneedles may have porosity in the range of 10-45%. Pore diameter of20-200 nm can easily be achieved—so meso- and macroporous materials canbe made (when nanocrystalline, e.g. zirconia, powders are used porediameters of 10 nm are possible).

Such microneedles may be used to produce suitable skin patches withimproved quality. It is found that use of additives in the ceramicmicroneedle yielding a ceramic composite microneedle having particlesize in the nano-meter range improves surface qualities of themicroneedles, because surface properties of such microneedles whichpores are at least partially filled with nano-meter material aresubstantially improved simplifying protrusion of the microneedle arraythrough a skin barrier. Such microneedles are preferable for suitingdemands of diagnostics or therapy.

In a particular embodiment of the microneedle array according to theinvention said set of microneedles comprises microneedles of differentlengths. This may be advantageous when different microneedles have topenetrate to a different depth, or, when the longer microneedles areused to pre-stretch the skin prior to penetration of shortermicroneedles. The shorter microneedles may be drug carrying, or passivefor extracting a body fluid or for providing an electrical contact withthe body. In the latter case it is preferable that the microneedlescomprise or are coated with an electrically conducting material, forexample Ag.

It is found to be advantageous when said plurality of microneedlescomprises at least a first and a second microneedle being arrangedsubstantially opposite to each other on a periphery of said set, whereinsaid at least the first and the second microneedles have increasedlength with respect to overall microneedles of said set.

Such configuration is used to pre-stretch the skin before the shortermicroneedles enter the skin barrier. It is further possible that thelonger microneedles located at the periphery have a different, forexample greater, cross-section than the shorter microneedles. This mayimprove pre-stretching of the skin. Preferably, the microneedle arrayaccording to the invention comprises microneedles with the aspect rationin the range of 3-6, whereby the length of said at least the first andthe second microneedles is at least 1-10% larger than the length of theoverall microneedles of the set. Larger differences, of course, can bealso achieved, as for example when flat-tips being produced onto theplane area of the silicon working surface are combined with the obliquetips resulting from the overlay with the pits in the silicon workingsurface. Additionally or alternatively, the microneedles are formed withoblique end surfaces conceived to interact with a material barrier. Withthis geometry penetration through a material barrier, for example theskin, is further improved. It will be appreciated that the obliquesurfaces of such elongated microneedles may be facing each other, or maybe opposed to each other.

A system for transporting substances across a material barrier accordingto the invention comprises a microneedle array according to the foregoing.

A system for extracting or for injecting a fluid according to theinvention comprises a microneedle array according to the foregoing.

A system for measuring an electric signal using an electrode accordingto the invention comprises an electrode formed at least partially from amicroneedle array as discussed in the foregoing. Such system may be usedfor recording of an electrical signal representative of a physiologicalparameter. For example, such system may be used for recording orlong-term monitoring of EEG signal, signal related to cardiac activity,myographic signal, or the like. Recording to the EEG using methods knownin the art is time consuming, in particular regarding mounting of theelectrodes and skin preparation. An electrode comprising a microneedlearray, as is discussed with reference to the foregoing, substantiallyreduces the mounting time and circumvents the need for skin preparation,in particular removal of part of the epidermis by scrubbing.

It has been demonstrated that the signal-to-noise ratio of themicroneedle-based electrodes used for receiving an electric signalrelated to a vital sign is substantially the same as the signal-to-noiseration of the conventionally used macroscopic electrodes. Therefore,there is substantially no trade-off between the reduction of themounting and preparation time and resulting quality of the collectedsignal, making such system advantageous for investigating and/ormonitoring of a vital sign of adults and neonates. The system mayprovide in a further embodiment the use of such microneedle arraycomprising electrodes for in-home environment patient monitoring.

These and other aspects of the invention will be further discussed withreference to drawings. It will be appreciated that the drawings arehereby presented for illustrative purposes only and may not be used forlimiting the scope of the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic isometric view of a nano-material embedded skinpatch in accordance with a preferred embodiment of the presentinvention;

FIG. 1 a presents a scanning electron micrograph of a microneedle arrayconfiguration;

FIG. 1 b presents a scanning electron micrograph depict porosity of aceramic microneedle array provided with the method of the invention;

FIG. 1 c presents an embodiment of a resulting cut into a skin modelsystem obtainable with the microneedle array of FIG. 1 a.

FIG. 2 is a schematic cross-section view of a wafer coated with a thinlayer of Silicon Nitride that may be used in the construction of theskin patch of FIG. 1;

FIG. 3 is a schematic cross-sectional view of the wafer of FIG. 2 with alayer of radiation sensitive material coating the layer of SiliconNitride;

FIG. 4 is a schematic cross-sectional view of the wafer of FIG. 3 with apatterned radiation sensitive material;

FIG. 5 is a schematic cross-sectional view of the wafer of FIG. 4 postetching, wherein an array of openings in the Silicon Nitride layer iscreated;

FIG. 6 is a schematic cross-sectional view of the wafer of FIG. 5 afterwet etching for creating grooves or pits therein according to thearrayed openings in the Silicon Nitride layer.

FIG. 7 is a schematic isometric view of the wafer of FIG. 6 depicting adetail A-A.

FIG. 8 is a further schematic cross-section view of the wafer of FIG. 7.

FIG. 9 is a schematic cross-section view of the wafer of FIG. 8 having athick layer of photoresist spin-coated thereon;

FIG. 10 is a schematic isometric view of the wafer of FIG. 9 showing anembodiment of a layout of the microneedle array by referring to thedetail A-A;

FIG. 11 is a schematic cross-sectional view of the wafer of FIG. 10after selectively irradiation and developing of the thick layer ofphotoresist, defining a form of inverted microneedle structures;

FIG. 11 a is a schematic cross-section view of the wafer of FIG. 10after dispensing, overlay, exposing a second layer of photoresist;

FIG. 11 b is a schematic cross section view of the wafer of FIG. 10processed according to FIG. 11 a, yielding a hard-mold with additionalprotrusions, for forming flow channel across a microneedle extendinginto the base plate.

FIG. 11 c is a schematic cross section view of the wafer of FIG. 10filled with PDMS.

FIG. 12 is a schematic cross-sectional view of a wafer having aninverted microneedle structure disposed thereon.

FIG. 13 is a schematic cross-sectional view of the replicated soft-molddefining the shape of the microneedles.

FIG. 14 is a schematic cross-section view of a further embodiment of awafer;

FIG. 15 is a schematic cross-section view of a still further embodimentof a wafer;

FIG. 16 is a schematic cross-section of a released production mold.

FIG. 17 is a schematic cross-section of a production mold covered withan anti-adhesive layer.

FIG. 18 is a schematic cross-section of a production mold filled with afiller material.

FIG. 19 is a schematic cross-section of a micro-needle array.

FIG. 20 is a schematic view of a functionalization step.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic isometric view of a skin patch using a microneedlearray in accordance with a preferred embodiment of the presentinvention. The skin patch 1 comprises a platform for placing and,preferably, fixating the skin patch 1 to the skin. The platform 18 ispreferably manufactured from a biocompatible material, which may bearranged breathable for ensuring durable application of the skin patchon the skin. This may be advantageous in case when the skin patch 1 isconceived to be used as electrodes for conducting EEG, myography or anyother suitable electric interaction with the skin.

The skin patch 1 further comprises a set of preferably arrayedout-of-plane microneedles 16 inherently integrated with the base plate.In accordance with the invention the microneedles 16 comprise porousceramic or porous ceramic composite material, for examplepolymer-ceramic material. The microneedles 16 may be provided with asubstance conceived to be transported through a skin barrier or with asubstance having a specific binding with a further substance conceivedto be extracted through the skin barrier. Such substance may be aprotein or other molecule, or molecular complex, including architecturesbased on liposome or polyelectrolyte chemistry suitable for therapeutictreatment and targeting. On the other hand such compound can interactwith compounds in the body fluid, for example for the selective bindingof a specific protein which has been identified as a biomarker.

It is possible that the array of microneedles 16 comprises sub-regionshaving different functionality. For example, the sub-region 10 may beeventually arranged with increased or decreased porosity in relation tothe overall microneedles of the array 16. Such porosity modulation maybe performed during a later processing step, for example duringfunctionalization, as described with reference to FIG. 20. Preferably,the microneedle array 16 comprises a suitable plurality of elongatedmicroneedles 12 for simplifying skin penetration, as it has been foundthat by providing such elongated microneedles the skin is pre-stretchedprior to it being at least partially protruded by the overallmicroneedles.

It will be appreciated that according to the invention the microneedlesarray may be limited to a set 12, formed in a cavity of a Si-wafer. Inaddition, in accordance with the invention, a wide range of specificarrangements of the microneedle tips is feasible. For example, themicroneedles, forming a set 12 may have tips oriented upwardly.Secondly, the tips may be formed obliquely either facing each other orbeing oriented outwardly from adjacent microneedle tips forming the set12. Usually the set 12 comprises 4 microneedles. Such grouping isreferred to as a sub-set. As has been explained earlier, a pitch betweenthe sub-groups 12 of the microneedle array may correspond to the pitchof the openings in a mask used for forming respective cavities in theSi-wafer. The pitch between the microneedles of the sub-set is afraction of the pitch between the sub-sets. Preferably, the microneedlesforming the sub-set are arranged to be substantially symmetricallydistributed over the cavity in the Si-wafer. More details on thepossible arrangements of the microneedles will be discussed withreference to FIGS. 1 a-1 c.

Preferably, a sub-set of elongated microneedles is arranged at peripheryof the array 16, notably diametrically dislocated from each other. Inaddition, the array 16 may comprise one or more microneedles 14 ofdistinguished geometry, that is of a geometry which may be substantiallydifferent from the geometry of the overall microneedles of the array 16.This may be advantageous in cases when such one or more microneedles 14have a different purpose than the overall microneedles. For example,delivery of different vaccines or sampling at different time intervals.

FIG. 1 a presents a scanning electron micrograph of a microneedle arrayconfiguration. In this particular embodiment, one of the possiblemicroneedle array configurations is shown depicting groups ofmicroneedles 12 having oblique end surfaces pointing inwardly. It willbe appreciated that the hard mold design may be suitably altered forproviding microneedles with oblique tips pointing outwardly. However, itis also possible to design a mask for providing microneedles arraywherein individual microneedles comprise tip shapes of differentconfiguration. Generally, such arrangement is advantageous formicroneedle arrays wherein individual microneedles have differentpurpose. For example, when some microneedles are used for cutting theskin and the other microneedles are used for transporting of a substanceacross the skin, both injecting and extracting being contemplated.

It will be appreciated that although the scale of FIG. 1 a is 500micrometer in 1.4 cm of the picture, no particular limitation on themicroneedle sizing may be inferred. FIG. 1 b further shows a detail ofthe intrinsic porosity of the alumina filler after drying, recovery fromthe soft production mold and sintering at high temperature. In thisparticular embodiment, which is presented with a considerably highermagnification than that of FIG. 1 a, trace amounts of Kaolin have beenadded to the ceramic slurry. FIG. 1 c presents an embodiment of aresulting cut into a skin model system obtainable with the microneedlearray of FIG. 1 a. FIG. 1 c depicts with a considerably highermagnification as shown in FIG. 1 a the penetration marks P1, P2 postmicroneedle insertion into a skin model system, wherein the microneedlearray configuration relates to a set of 4 microneedles, depicted by 12in FIG. 1 a. In this example an elastomer (PDMS) has been used to mimicthe skin reaction. The marks P1, P2 are at microscale and refer to thepenetration marks similar to the small insertion wounds that would begenerated when the microneedle array is used to penetrate human skin. Itis seen that these marks are smaller and smoother that the cutting marksobtainable with conventional flat tips. Such tip configuration whereintips of the microneedles are oblique and several microneedles worktogether in a small group 12 during insertion is preferable for skinpenetration in medical applications. In this respect inward or outwardorientation is preferable than arbitrary or one-sided orientation.

FIG. 2 is a schematic cross-section view of a Si wafer 20 coated with aSilicon Nitride layer 22 which may be used in the fabrication of a hardmold for providing a soft production mold for producing the skin patchof FIG. 1.

In accordance with the method of the invention a silicon wafer 20 isselected for providing a working surface for forming a hard master mold.The silicon wafer 20 is coated with silicon nitride thin-film coating,which may be used as a masking layer. FIG. 3 is a schematiccross-sectional view of the wafer of FIG. 2 with a layer of radiationsensitive material 24 coating the layer of Silicon Nitride. Theradiation sensitive layer 24 is preferably suitable for performingultra-violet lithography.

FIG. 4 is a schematic cross-sectional view of the Si wafer 20 of FIG. 3with a patterned radiation sensitive material 24 after a suitablelithographic step has been performed. It is seen that openings 26 areformed in the radiation sensitive layer 24 for selectively removingsilicon nitride layer 22. FIG. 5 is a schematic cross-sectional view ofthe Si wafer 20 of FIG. 4 post etching, wherein an array of openings inthe silicon nitride layer 26 is created. Preferably, for this purposereactive ion etching is used. It will be appreciated that the openingsare provided at places spatially matching (aligned) with specificorientation of crystalplanes of the Si-wafer, like (100). From thecrystallography it follows that such openings will yield specificstructures (for example, pyramidal pits determined by the selectiveetching of the 100 and the 111 planes in the silicon) have a pre-definedpitch and width, which may define the resulting geometry of themicroneedle array. It will be appreciated that the technology ofalignment of the mask with the internal structures is known per se, forexample such alignment may be carried out using microscope-augmentedmask alignment between a standardized silicon wafer and a chromium masklayout).

FIG. 6 is a schematic cross-sectional view of the wafer 20 of FIG. 5after wet etching for creating grooves 30 or pits therein according tothe arrayed openings 26 in the silicon nitride layer 28, shown in FIG.5. Preferably an anisotropic wet etching using potassium hydroxide KOHis used.

FIG. 7 is a schematic isometric view of the wafer of FIG. 6 depicting adetail A-A running through a two-dimensional image of the wafer 32. Itis seen that grooves 30 having dimension (x, y) are spaced in the waferhaving respective pitches in x-direction P_(x) and y-direction P_(y),which may correspond to the pitch of the internal structures of the Siwafer. The properties of thus formed grooved surface (pre-patternedsilicon working surface) may be modified by using an anti-reflectionlayer 34 (see FIG. 8). The anti-reflection layer 34 serves to mitigateghost features occurring during lithography, which advantageouslyimproved geometric properties of the microneedle array. Preferably, forthe anti-reflection layer titanium silicide is used.

FIG. 9 is a schematic cross-section view of the wafer of FIG. 8 having alayer of photoresist 36 spin-coated thereon. Preferably, the layer ofphotoresist has a thickness in the range of 50-360 micrometers measuredfrom a planner plane of the working surface, whereby for the resistconventional SU-8 100 material is used. The thickness of the photoresistmaterial 36 determines the length of the resulting microneedle array.

FIG. 10 is a schematic isometric view of the wafer of FIG. 9 showing anembodiment of a layout of the microneedle array by referring to thedetail A-A. Exposed resist 38 shows a latent image of the invertedmicroneedles arranged in a pre-determined geometry having pitchparameters R_(x), R_(y) and width parameters W_(x), W_(y), whichcorresponds to the pitch and width of internal structures of the Siwafer used for manufacturing of the hard master mold.

FIG. 11 is a schematic cross-sectional view of the wafer of FIG. 10after selectively irradiation and developing of the layer of photoresist36 yielding exposed resist 38, defining a form of inverted microneedlestructures as openings 40 in the exposed resist 38. In the context ofthe present application this structure is referred to as a hard mastermold.

In accordance with a further embodiment of the method according to theinvention, the hard master mold depicted in FIG. 11 is replicated twicefor yielding a soft production mold which is used for manufacturingceramic or ceramic composite microneedles inherently integrated into abase plate.

FIG. 11 a is a schematic cross-section view of the wafer of FIG. 10after dispensing, overlay, exposing a second layer of photoresist 70through a mask 69. The photoresist 70 may be subsequently developedtogether with the first layer 38 that had been previously selectivelyexposed. FIG. 11 b is a schematic cross section view of the wafer ofFIG. 10 processed according to FIG. 11 a post development, delivering ahard-mold with additional protrusions 71, which form respectivemicrosized flow channels across a microneedle extending into the baseplate. FIG. 11 c is a schematic cross section view of the wafer of FIG.10 processed according to FIG. 11 a and FIG. 11 b subsequently filledwith PDMS for generating the soft intermediate mold 72. For clarity onlya portion of the filling is drawn. Detail Y further depicts the copyfrom intermediate mold 72 and recovery of the soft production mold 73containing a protrusion within the inverted shape of a microneedle.Subsequently, the ceramic filler is dispensed on the production mold 73,and the ceramic green tape 74, showing the flow-through channel in themicroneedle and the base plate, is recovered from the production mold73. For clarity only portions of the microneedle array are drawn inFIGS. 11 a-11 c.

FIG. 12 is a schematic cross-sectional view of the wafer 32 and exposedresist 38, openings of which are filled with a suitable filler material42 for yielding an intermediate soft mold replicating the geometry ofthe hard master mold. Preferably for the filler material PDMS isselected to provide a flexible intermediate mold.

FIG. 13 is a schematic cross-sectional view of the intermediate softmold 42 having the exact shape of the microneedles corresponding to thegeometry of the master mold shown in FIG. 11. It will be appreciatedthat replication process is known per se in the art and will not beexplained here in detail.

FIG. 14 is a schematic cross-section view of a further embodiment of theintermediate mold provided with an anti-adhesion layer 44. This is foundto be advantageous for simplifying release of the production mold whichis formed using the intermediate mold.

FIG. 15 is a schematic cross-section view of a view depicting the softproduction mold provided using a filling material 46 arranged on theintermediate mold. Preferably, also for the filling material forming theproduction mold PDMS is selected for yielding a flexible, preferablyelastic production mold.

FIG. 16 is a schematic cross-section of a released soft production mold46, which may be covered with an anti-adhesive layer 48, as is depictedin FIG. 17. Use of the anti-adhesive layer may facilitate an easyremoval of the ceramic or ceramic composite microneedle array from thesoft production mold.

FIG. 18 is a schematic cross-section of the soft production mold 46 afilled with a filler material 50. The filler material 50 is provided inabundance thereby enabling formation of the microneedle array inherentlyintegrated with a base plate in a single manufacturing step. Inaccordance with the invention for the filler material 50 a water oralcohol based ceramic or polymer-ceramic slurry is selected. It ispossible to use alumina, zirconia or hydroxyapatite for yieldingnanocomposite or nanohybride filler material. The slurry may containmetal particles or other additives for imparting additionalfunctionality.

By way of example, a slurry to be used as the filler material may beprovided as follows. Alcohol based polymer-precursor solution withadditives is prepared. Hereby a polymeric binder, for examplepolyvinylbutural, is used in desired amounts and molecular weight apt totailor the porous structure of final material. Subsequently ceramicpowder with, for example, approx. 300-500 nm grain size in case ofalumina is added to the binder solution. Using other material systems,for example zirconia, the grain size range can be around 50 nm or evensmaller. A range of 0.5-7% of additives can be introduced, for examplenatural occurring oils, which enhance green tape properties and releasebehavior and particles of minerals, preferably having a diameter being5-30% smaller than the main used ceramic compound. The additionalmineral motivates the diffusion properties at the ceramic grainboundaries during sintering.

Regarding mineral additives, it is found that by adding at least of 0.1Wt % of Si to the original slurry improved robustness of the finalmicroneedle array yet preserving its porosity. With slurry havingapproximately 1 Wt % of Si inside of the material after sintering astill better result is achieved. It is found that advantageously theSi-based additive should be about 0.1-10 Wt % of the slurry, preferablyabout several weight percents, more preferably about 1 Wt %. Therefore,this tuning of the physical properties of the ceramic material offersfunctionalization of the microneedle array in the sense that itsproperties may easily be tailored for a specific envisaged application.Similarly, metals may be used as additives.

FIG. 19 is a schematic cross-section of a resulting micro-needle array50 integrated in a base plate and having porous structure, as depictedin detail X. Preferably, the filler material is supplemented with one ormore additives for suitably tailoring properties of the microneedles asis explained in the foregoing. Preferably, for the additive asilica-based mineral, by means of example, Kaolin is selected. Hence, asuch received integrated microneedle array in its green-statesubsequently undergoes an according drying procedure, which may includestep-wise application of a temperature profile up to very hightemperatures known in the art of ceramic sintering, giving the materialits final properties.

FIG. 20 is a schematic view of a functionalization step. Chemical orphysical properties of a microneedle array 50 comprising a ceramic or aceramic composite material may be advantageously tuned on demand bymeans of a functionalization step using an additive. For this purpose asurface of the microneedles may be coated with a suitable coating 54, 56supplied from a suitable source 52. The suitable coating may bedeposited as a monolayer, or, alternatively it may be deposited as athin layer, having thickness in the range of a few nanometers. Sectionsof the array, for example individual microneedles of the array, may bemodified selectively. Further, for example, the coating 54, 56 maycomprise specific molecules, like pyrene for enabling specific bindingcharacteristics. Alternatively, or additionally the coating moleculesmay relate to surface immobilized molecules. It will be appreciated thatfunctionalization may be achieved not only by coating, but also byproviding a substance conceived to at least partially fill the pores inthe microneedles. Such substance may relate to a drug, or to anothermatter, for example to change hydrophilic or hydrophobic surfaceproperties of the microneedle array by changing the surface charge ofthe hydrophilic alumina, e.g. applying titanium oxide formed, forexample, from a sol-gel. Other example may be the modification ofsurface properties by liposome or polyelectrolyte chemistry capable ofincorporating selective molecules suitable for specific targeting orincreased bioavailability. Polyelectrolytes may incorporate molecules byclick-chemistry.

It will further be appreciated that the method according to theinvention is also applicable to fabrication of polymer microneedlearrays, wherein instead of alcohol based ceramic or polymer-ceramicslurry a polymer material is selected. As a result, a new technologicalsequence is provided for mass production of polymer microneedle arrayswherein said production sequence is relatively cheap and providesmicroneedles with tunable properties. For example, at least thefollowing properties may be alterable on demand: tip shape orarrangements of a variety of tip shapes within one array, diameter ofthe microneedles, their length, density in the array, orientation of theoblique tips with respect to each other.

While embodiments of the invention disclosed herein are presentlyconsidered to be preferred, various changes and modifications can bemade without departing from the scope of the invention. Those skilled inthe art will appreciate that the figures show a limited number ofmicroneedles in an array. However, a large number of microneedles perarray arranges in different spatial configurations may be used. Thescope of the invention is indicated in the appended claims, and allchanges that come within the meaning and range of equivalents areintended to be embraced therein.

What is claimed is:
 1. A microneedle array comprising a base plate and aset of microneedles integrated with the base plate, wherein themicroneedles comprise a porous ceramic material or a porous ceramiccomposite material having pores, the diameter of the pores ranging from10 to 200 nanometer.
 2. The microneedle array according to claim 1,wherein the microneedles substantially seamlessly transit into the baseplate.
 3. The microneedle array according to claim 1, wherein said setof microneedles comprises microneedles of different lengths.
 4. Themicroneedle array according to claim 3, wherein said set of microneedlescomprises at least a first and a second microneedle being arrangedsubstantially opposite to each other on a periphery of said set, whereinsaid at least the first and the second microneedles have increasedlength with respect to overall microneedles of said set.
 5. Themicroneedle array according to claim 4, wherein the length of said atleast the first and the second microneedles is at least 1-10% largerthan the length of the overall microneedles of the set.
 6. Themicroneedle array according to claim 1, wherein the microneedles areformed with oblique tips conceived to interact with a material barrier.7. The microneedle array according to claim 6, comprising one or moresub-sets with microneedles having oblique tips oriented inwardly oroutwardly.
 8. The microneedle array according to claim 1 whereinmicroneedles comprise have tip shapes of different configuration.
 9. Themicroneedle array according to claim 1, wherein at least one microneedlecomprises a channel for conducting a fluid therethrough.
 10. Acomposition comprising a microneedle array according to claim 1, whereinsaid composition comprises a substance conceived to be transportedthrough a material barrier or conceived to have a specific binding to afurther substance to be extracted via the material barrier using saidmicroneedles.
 11. The composition according to claim 10, wherein themicroneedles comprises pores at least partially filled with thesubstance.
 12. The composition according to claim 10, wherein themicroneedles comprise subsets of microneedles having differentfunctionality and/or different geometry.
 13. A system for enablingtransport of a substance through a material barrier comprising amicroneedle array according to claim
 1. 14. A system for measuring anelectric signal using an electrode, wherein the electrode comprises ofat least one of the microneedles in the microneedle array according toclaim 1.